1. Field of the Invention
This invention relates to materials and methods for preparing P-chirogenic phospholane ligands and to their use in asymmetric syntheses, including the enantioselective hydrogenation of prochiral olefins to prepare pharmaceutically useful compounds such as pregabalin.
2. Discussion
Asymmetric catalysis is often the most efficient method for the synthesis of enantiomerically enriched compounds because a small amount of a chiral catalyst can be used to produce a large quantity of a chiral target molecule. Over the last two decades, more than a half-dozen commercial industrial processes have been developed that use asymmetric catalysis as the key step in the production of enantiomerically pure compounds with much effort focused on developing new asymmetric catalysts for these reactions. See, e.g., J. D. Morrison, ed., Asymmetric Synthesis 5 (1985); B. Bosnich, ed., Asymmetric Catalysis (1986); H. Brunner, Synthesis 645 (1988); R. Noyori & M. Kitamura, in R. Scheffold, ed., Modern Synthetic Methods 5:115 (1989); W. A. Nugent et al., Science 259:479 (1993); I. Ojima, ed., Catalytic Asymmetric Synthesis (1993); R. Noyori, Asymmetric Catalysis In Organic Synthesis (1994). For more recent examples, see “Special Feature Section: Homogeneous Transition Metal-Catalyzed Reactions,” Organic Process Research and Development 7 (3):341-445 (2003).
Chiral phosphine ligands have played a significant role in the development of novel transition metal catalyzed asymmetric reactions to produce enantiomeric excess of compounds with desired activities. The first successful attempts at asymmetric hydrogenation of eneamide substrates were accomplished in the late 1970s using chiral bisphosphines as transition metal ligands. See, e.g., B. D. Vineyard et al., J. Am. Chem. Soc. 99 (18):5946-52 (1977); W. S. Knowles et al., J. Am. Chem. Soc. 97 (9):2567-68 (1975). Since these first published reports, there has been a continuous expansion of research related to the synthesis of new chiral bisphosphine ligands for asymmetric hydrogenations and other chiral catalytic transformations. See I. Ojima, ed., Catalytic Asymmetric Synthesis (1993); D. J. Ager, ed., Handbook of Chiral Chemicals (1999).
Much of the current interest in new chiral ligands and catalysts results from their use in preparing enantiomerically enriched or enantiopure drugs. One such drug is pregabalin, (S)-3-aminomethyl-5-methyl-hexanoic acid, which is the active pharmaceutical ingredient in LYRICA®. Pregabalin is related to the endogenous inhibitory neurotransmitter γ-aminobutyric acid (GABA), which is involved in the regulation of brain neuronal activity. Pregabalin exhibits anti-seizure activity, as described in U.S. Pat. No. 5,563,175 to R. B. Silverman et al., and is thought to be useful for treating, among other conditions, pain, physiological conditions associated with psychomotor stimulants, inflammation, gastrointestinal damage, alcoholism, insomnia, and various psychiatric disorders, including mania and bipolar disorder. See, respectively, U.S. Pat. No. 6,242,488 to L. Bueno et al., U.S. Pat. No. 6,326,374 to L. Magnus & C. A. Segal, and U.S. Pat. No. 6,001,876 to L. Singh; U.S. Pat. No. 6,194,459 to H. C. Akunne et al.; U.S. Pat. No. 6,329,429 to D. Schrier et al.; U.S. Pat. No. 6,127,418 to L. Bueno et al.; U.S. Pat. No. 6,426,368 to L. Bueno et al.; U.S. Pat. No. 6,306,910 to L. Magnus & C. A. Segal; and U.S. Pat. No. 6,359,005 to A. C. Pande, which are herein incorporated by reference in their entirety and for all purposes.
A recent U.S. patent describes a method of making pregabalin and other chiral compounds via asymmetric hydrogenation of a cyano-substituted olefin to produce a chiral cyano precursor of (S)-3-aminomethyl-5-methyl-hexanoic acid. See U.S. Pat. No. 6,605,745 to G. S. Hoge, II & O. P. Goel (the '745 patent), which is assigned to the Warner-Lambert Company LLC and is herein incorporated by reference in its entirety for all purposes. The cyano precursor is subsequently reduced to give enantiomerically-enriched pregabalin in high yield. According to the '745 patent, the asymmetric hydrogenation employs a chiral catalyst, which is comprised of a transition metal (e.g., rhodium) bound to a P-chirogenic bisphospholane ligand, such as 1,2-bis((1R,2R)-2-benzylphospholanyl)ethane,
Besides alkanediyls, such as the ethanediyl in Formula 1, the '745 patent discloses other bridges that link the phosphorus atoms, including substituted and unsubstituted phen-1,2-diyl bridges as shown in the compound of Formula 2,

The '745 patent discloses numerous methods for making P-chirogenic bisphospholane ligands. One useful method employs a CuCl2 promoted oxidative coupling of a methyl anion of the compound of Formula 3,
which is obtained by treating the compound of Formula 3 with a strong base, such as s-BuLi. Although this approach is useful for preparing P-chirogenic bisphospholanes similar to the compound of Formula 1, such approaches are less useful for ligands exemplified by Formula 2. Therefore, it would be desirable to develop a general technique for preparing P-chirogenic bisphospholanes.